This Article Full Text Full Text (PDF) All Versions of this Article: 108/16/1994    most recent 01.CIR.0000092886.52404.50v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Phillips, J. W. Articles by Sarembock, I. J. Search for Related Content PubMed PubMed Citation Articles by Phillips, J. W. Articles by Sarembock, I. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Related Collections Restenosis Animal models of human disease Type 2 diabetes Mechanism of atherosclerosis/growth factors

(Circulation. 2003;108:1994.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Rosiglitazone Reduces the Accelerated Neointima Formation After Arterial Injury in a Mouse Injury Model of Type 2 Diabetes

J. William Phillips, MD; Kurt G. Barringhaus, MD; John M. Sanders, BS; Zandong Yang, MD; Meng Chen, MD; Sean Hesselbacher, BS; Ann C. Czarnik, BS; Klaus Ley, MD; Jerry Nadler, MD; Ian J. Sarembock, MB, ChB, MD

From the Departments of Medicine (J.W.P., K.G.B., J.M.S., S.H., A.C.C., J.N., I.J.S.), Cardiovascular Division, and Cardiovascular Research Center (K.L., I.J.S.), Division of Endocrinology (Z.Y., M.C., J.N.), and Department of Biomedical Engineering (K.L.), University of Virginia Health System, Charlottesville, Va.

Correspondence to Ian J. Sarembock, MD, Cardiovascular Division, University of Virginia Health System, Box 800158, Charlottesville, VA 22908-0158. E-mail ijs4s{at}virginia.edu

Received September 24, 2002; de novo received March 20, 2003; revision received June 16, 2003; accepted June 17, 2003.

Background— Hyperglycemia (HG) and hyperinsulinemia (HI) may be factors enhancing the atherosclerotic complications of diabetes. We hypothesized that specific feeding of C57BL/6 apolipoprotein (apo) E^-/- mice would alter their metabolic profiles and result in different degrees of neointima (NI) formation. We additionally hypothesized that an insulin-sensitizing agent (rosiglitazone) would prevent the development of type 2 diabetes and reduce neointima formation after carotid wire injury measured at 28 days.

Methods and Results— Fasting glucose and insulin levels were elevated in the Western diet (WD) group, with a trend toward higher insulin levels and euglycemia in the fructose diet (FD)–fed mice. NI formation was exaggerated in the WD group compared with the FD or chow control groups. In the WD mice given rosiglitazone, glucose and insulin levels remained normal and NI formation was significantly reduced, as was NI macrophage content.

Conclusions— These findings demonstrate that apoE^-/- mice fed a WD develop type 2 diabetes with an exaggerated NI response to injury. FD mice maintain euglycemia but develop insulin resistance, with an intermediate degree of NI growth compared with chow diet controls. Rosiglitazone prevents the development of hyperglycemia and hyperinsulinemia and normalizes the insulin release profile in the apoE^-/-, WD-fed mouse and significantly reduces NI formation by 65% after carotid wire injury while reducing macrophage infiltration. These data support the hypothesis that type 2 diabetes in the setting of elevated cholesterol accelerates the response to vascular injury and suggest that agents that improve insulin sensitivity may have therapeutic value in reducing restenosis in type 2 diabetes.

Key Words: angioplasty • drugs • hypercholesterolemia • diet • diabetes mellitus

This article has been cited by other articles:

				G. Li, J. M. Sanders, M. H. Bevard, Z. Sun, J. W. Chumley, E. V. Galkina, K. Ley, and I. J. Sarembock CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular Injury Am. J. Pathol., April 1, 2008; 172(4): 1141 - 1152. [Abstract] [Full Text] [PDF]

				G. Kronke, A. Kadl, E. Ikonomu, S. Bluml, A. Furnkranz, I. J. Sarembock, V. N. Bochkov, M. Exner, B. R. Binder, and N. Leitinger Expression of Heme Oxygenase-1 in Human Vascular Cells Is Regulated by Peroxisome Proliferator-Activated Receptors Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1276 - 1282. [Abstract] [Full Text] [PDF]

				G. Hansmann, R. A. Wagner, S. Schellong, V. A. de Jesus Perez, T. Urashima, L. Wang, A. Y. Sheikh, R. S. Suen, D. J. Stewart, and M. Rabinovitch Pulmonary Arterial Hypertension Is Linked to Insulin Resistance and Reversed by Peroxisome Proliferator-Activated Receptor-{gamma} Activation Circulation, March 13, 2007; 115(10): 1275 - 1284. [Abstract] [Full Text] [PDF]

				I. Imayama, T. Ichiki, K. Inanaga, H. Ohtsubo, K. Fukuyama, H. Ono, Y. Hashiguchi, and K. Sunagawa Telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator-activated receptor {gamma} Cardiovasc Res, October 1, 2006; 72(1): 184 - 190. [Abstract] [Full Text] [PDF]

				S. Lim, C. J. Jin, M. Kim, S. S. Chung, H. S. Park, I. K. Lee, C. T. Lee, Y. M. Cho, H. K. Lee, and K. S. Park PPAR{gamma} Gene Transfer Sustains Apoptosis, Inhibits Vascular Smooth Muscle Cell Proliferation, and Reduces Neointima Formation After Balloon Injury in Rats Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 808 - 813. [Abstract] [Full Text] [PDF]

				A. G. Howarth, W. B. Wiehler, M. Pannirselvam, Y. Jiang, J. P. Berger, D. Severson, T. J. Anderson, and C. R. Triggle A Nonthiazolidinedione Peroxisome Proliferator-Activated Receptor {gamma} Agonist Reverses Endothelial Dysfunction in Diabetic (db/db-/-) Mice J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 364 - 370. [Abstract] [Full Text] [PDF]

				N. Hennuyer, A. Tailleux, G. Torpier, H. Mezdour, J.-C. Fruchart, B. Staels, and C. Fievet PPAR{alpha}, but not PPAR{gamma}, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1897 - 1902. [Abstract] [Full Text] [PDF]

				M. H. Clough, D. J. Schneider, B. E. Sobel, M. F. White, M. P. Wadsworth, and D. J. Taatjes Attenuation of Accumulation of Neointimal Lipid by Pioglitazone in Mice Genetically Deficient in Insulin Receptor Substrate-2 and Apolipoprotein E J. Histochem. Cytochem., May 1, 2005; 53(5): 603 - 610. [Abstract] [Full Text] [PDF]

				V. A. Fonseca, J. Diez, and D. B. McNamara Decreasing Restenosis Following Angioplasty: The potential of peroxisome proliferator-activated receptor {gamma} agonists Diabetes Care, November 1, 2004; 27(11): 2764 - 2766. [Full Text] [PDF]

				Y. Naka, L. G. Bucciarelli, T. Wendt, L. K. Lee, L. L. Rong, R. Ramasamy, S. F. Yan, and A. M. Schmidt RAGE Axis: Animal Models and Novel Insights Into the Vascular Complications of Diabetes Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1342 - 1349. [Abstract] [Full Text] [PDF]

				K. S. Meir and E. Leitersdorf Atherosclerosis in the Apolipoprotein E-Deficient Mouse: A Decade of Progress Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1006 - 1014. [Abstract] [Full Text] [PDF]

				C.-H. Wang, N. Ciliberti, S.-H. Li, P. E. Szmitko, R. D. Weisel, P. W.M. Fedak, M. Al-Omran, W.-J. Cherng, R.-K. Li, W. L. Stanford, et al. Rosiglitazone Facilitates Angiogenic Progenitor Cell Differentiation Toward Endothelial Lineage: A New Paradigm in Glitazone Pleiotropy Circulation, March 23, 2004; 109(11): 1392 - 1400. [Abstract] [Full Text] [PDF]